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Defining the boundaries of normal thrombin generation: investigations into hemostasis.

ABSTRACT: In terms of its soluble precursors, the coagulation proteome varies quantitatively among apparently healthy individuals. The significance of this variability remains obscure, in part because it is the backdrop against which the hemostatic consequences of more dramatic composition differences are studied. In this study we have defined the consequences of normal range variation of components of the coagulation proteome by using a mechanism-based computational approach that translates coagulation factor concentration data into a representation of an individual's thrombin generation potential. A novel graphical method is used to integrate standard measures that characterize thrombin generation in both empirical and computational models (e.g max rate, max level, total thrombin, time to 2 nM thrombin ("clot time")) to visualize how normal range variation in coagulation factors results in unique thrombin generation phenotypes. Unique ensembles of the 8 coagulation factors encompassing the limits of normal range variation were used as initial conditions for the computational modeling, each ensemble representing "an individual" in a theoretical healthy population. These "individuals" with unremarkable proteome composition was then compared to actual normal and "abnormal" individuals, i.e. factor ensembles measured in apparently healthy individuals, actual coagulopathic individuals or artificially constructed factor ensembles representing individuals with specific factor deficiencies. A sensitivity analysis was performed to rank either individual factors or all possible pairs of factors in terms of their contribution to the overall distribution of thrombin generation phenotypes. Key findings of these analyses include: normal range variation of coagulation factors yields thrombin generation phenotypes indistinguishable from individuals with some, but not all, coagulopathies examined; coordinate variation of certain pairs of factors within their normal ranges disproportionately results in extreme thrombin generation phenotypes, implying that measurement of a smaller set of factors may be sufficient to identify individuals with aberrant thrombin generation potential despite normal coagulation proteome composition.

SUBMITTER: Danforth CM

PROVIDER: S-EPMC3271084 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Defining the boundaries of normal thrombin generation: investigations into hemostasis.

Danforth Christopher M CM Orfeo Thomas T Everse Stephen J SJ Mann Kenneth G KG Brummel-Ziedins Kathleen E KE

PloS one 20120202 2

In terms of its soluble precursors, the coagulation proteome varies quantitatively among apparently healthy individuals. The significance of this variability remains obscure, in part because it is the backdrop against which the hemostatic consequences of more dramatic composition differences are studied. In this study we have defined the consequences of normal range variation of components of the coagulation proteome by using a mechanism-based computational approach that translates coagulation f ...[more]

PMID: 22319567

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Project description:Extracorporeal membrane oxygenation (ECMO) support has a high incidence of both bleeding and thrombotic complications. Despite clear differences in patient characteristics and pathologies between veno-venous (VV) and veno-arterial (VA) ECMO support, anticoagulation practices are often the same across modalities. Moreover, there is very little data on their respective coagulation profiles and comparisons of thrombin generation in these patients. This study compares the coagulation profile and thrombin generation between patients supported with either VV and VA ECMO. A prospective cohort study of patients undergoing VA and VV ECMO at an Intensive care department of a university hospital and ECMO referral centre. In addition to routine coagulation testing and heparin monitoring per unit protocol, thromboelastography (TEG), multiplate aggregometry (MEA), calibrated automated thrombinography (CAT) and von-Willebrand's activity (antigen and activity ratio) were sampled second-daily for 1 week, then weekly thereafter. VA patients had significantly lower platelets counts, fibrinogen, anti-thrombin and clot strength with higher d-dimer levels than VV patients, consistent with a more pronounced consumptive coagulopathy. Thrombin generation was higher in VA than VV patients, and the heparin dose required to suppress thrombin generation was lower in VA patients. There were no significant differences in total bleeding or thrombotic event rates between VV and VA patients when adjusted for days on extracorporeal support. VA patients received a lower median daily heparin dose 8500 IU [IQR 2500-24000] versus VV 28,800 IU [IQR 17,300-40,800.00]; < 0.001. Twenty-eight patients (72%) survived to hospital discharge; comprising 53% of VA patients and 77% of VV patients. Significant differences between the coagulation profiles of VA and VV patients exist, and anticoagulation strategies for patients of these modalities should be different. Further research into the development of tailored anticoagulation strategies that include the mode of ECMO support need to be completed.

Dataset Information

Defining the boundaries of normal thrombin generation: investigations into hemostasis.

Publications

Defining the boundaries of normal thrombin generation: investigations into hemostasis.

Similar Datasets

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